Frontiers in the physiology of male pattern androgenetic alopecia: beyond the androgen horizon.

Male pattern androgenetic alopecia (mpAGA), the most common form of hair loss in men, represents a heritable, androgen-dependent complex trait distinct from female pattern hair loss. Despite the psychosocial burden of mpAGA in some affected individuals and associations with other morbidities, we portray mpAGA as an essentially physiological phenomenon in which defined hair follicle (HF) populations in developmentally preprogrammed scalp skin regions undergo a dramatic, but reversible (mini)organ transformation in genetically predisposed individuals. Histologically, mpAGA exhibits progressive HF miniaturization (terminal-to-vellus conversion) and anagen shortening. Clinically, this results in a characteristic balding pattern of frontotemporal and vertex scalp skin, associated with telogen effluvium. It remains unclear how exactly androgens induce this phenotype, since neither androgen receptor polymorphisms nor changes in androgen serum or local androgen skin levels persuasively explain it. It also is as yet unresolved whether mpAGA-associated HF transformation and hair cycle changes are primarily driven by the HF mesenchyme, e.g., by excessive emigration, reduced inductive potential and premature senescence of dermal papilla fibroblasts, or by intraepithelial events such as prostaglandin D2-dependent reduced HF epithelial stem cell progenitor generation. While critically revisiting our limited current understanding of mpAGA physiology and the role of mpAGA-associated genes, we discuss potential targets for future therapeutic intervention beyond androgens and highlight selected dysregulated signaling pathways in mpAGA. We underscore mpAGA as an instructive, accessible model for interrogating underinvestigated physiological roles of immune cells, oxidative stress, aging/senescence, and the microbiome in human organ remodeling and hair cycle regulation and define major open research questions beyond androgen receptor-mediated signaling.